Ankle exoskeletons can now reduce the metabolic cost of walking in humans without leg disability, but the biomechanical mechanisms that underlie this augmentation are not fully understood. In this ...study, we analyze the energetics and lower limb mechanics of human study participants walking with and without an active autonomous ankle exoskeleton previously shown to reduce the metabolic cost of walking.
We measured the metabolic, kinetic and kinematic effects of wearing a battery powered bilateral ankle exoskeleton. Six participants walked on a level treadmill at 1.4 m/s under three conditions: exoskeleton not worn, exoskeleton worn in a powered-on state, and exoskeleton worn in a powered-off state. Metabolic rates were measured with a portable pulmonary gas exchange unit, body marker positions with a motion capture system, and ground reaction forces with a force-plate instrumented treadmill. Inverse dynamics were then used to estimate ankle, knee and hip torques and mechanical powers.
The active ankle exoskeleton provided a mean positive power of 0.105 ± 0.008 W/kg per leg during the push-off region of stance phase. The net metabolic cost of walking with the active exoskeleton (3.28 ± 0.10 W/kg) was an 11 ± 4 % (p = 0.019) reduction compared to the cost of walking without the exoskeleton (3.71 ± 0.14 W/kg). Wearing the ankle exoskeleton significantly reduced the mean positive power of the ankle joint by 0.033 ± 0.006 W/kg (p = 0.007), the knee joint by 0.042 ± 0.015 W/kg (p = 0.020), and the hip joint by 0.034 ± 0.009 W/kg (p = 0.006).
This study shows that the ankle exoskeleton does not exclusively reduce positive mechanical power at the ankle joint, but also mitigates positive power at the knee and hip. Furthermore, the active ankle exoskeleton did not simply replace biological ankle function in walking, but rather augmented the total (biological + exoskeletal) ankle moment and power. This study underscores the need for comprehensive models of human-exoskeleton interaction and global optimization methods for the discovery of new control strategies that optimize the physiological impact of leg exoskeletons.
Currently, the mobility of above-knee amputees is limited by the lack of available prostheses that can efficiently replicate biologically accurate movements. In this study, a powered knee prosthesis ...was designed utilizing a novel mechanism, known as a clutchable series-elastic actuator (CSEA).The CSEA includes a low-power clutch in parallel with an electric motor within a traditional series-elastic actuator. The stiffness of the series elasticity was tuned to match the elastically conservative region of the knee’s torque-angle relationship during the stance phase of locomotion. During this region, the clutch was used to efficiently store energy in the series elasticity. The fully autonomous knee prosthesis design utilized a brushless electric motor, ballscrew transmission and cable drive, as well as commercial electrical components. The knee was lighter than the eighth percentile and shorter than the first percentile male shank segment. The CSEA Knee was tested in a unilateral above-knee amputee walking at 1.3 m/s. During walking, the CSEA Knee provided biomechanically accurate torque-angle behavior, agreeing within 17% of the net work and 27% of the stance flexion angle produced by the biological knee. In addition, the process of locomotion reduced the net electrical energy consumption of the CSEA Knee. The knee’s motor generated 1.8 J/stride, and the net energy consumption was 3.6 J/stride, an order of magnitude less energy than previously published powered knee prostheses.
Epithelial-to-Mesenchymal Transition (EMT) and its reverse - Mesenchymal to Epithelial Transition (MET) - are hallmarks of cellular plasticity during embryonic development and cancer metastasis. ...During EMT, epithelial cells lose cell-cell adhesion and gain migratory and invasive traits either partially or completely, leading to a hybrid epithelial/mesenchymal (hybrid E/M) or a mesenchymal phenotype respectively. Mesenchymal cells move individually, but hybrid E/M cells migrate collectively as observed during gastrulation, wound healing, and the formation of tumor clusters detected as Circulating Tumor Cells (CTCs). Typically, the hybrid E/M phenotype has largely been tacitly assumed to be transient and 'metastable'. Here, we identify certain 'phenotypic stability factors' (PSFs) such as GRHL2 that couple to the core EMT decision-making circuit (miR-200/ZEB) and stabilize hybrid E/M phenotype. Further, we show that H1975 lung cancer cells can display a stable hybrid E/M phenotype and migrate collectively, a behavior that is impaired by knockdown of GRHL2 and another previously identified PSF - OVOL. In addition, our computational model predicts that GRHL2 can also associate hybrid E/M phenotype with high tumor-initiating potential, a prediction strengthened by the observation that the higher levels of these PSFs may be predictive of poor patient outcome. Finally, based on these specific examples, we deduce certain network motifs that can stabilize the hybrid E/M phenotype. Our results suggest that partial EMT, i.e. a hybrid E/M phenotype, need not be 'metastable', and strengthen the emerging notion that partial EMT, but not necessarily a complete EMT, is associated with aggressive tumor progression.
Prenatal ethanol exposure is associated with deficits in executive function such as working memory, reversal learning and attentional set shifting in humans and animals. These behaviors are dependent ...on normal structure and function in cholinergic brain regions. Supplementation with choline can improve many behaviors in rodent models of fetal alcohol spectrum disorders and also improves working memory function in normal rats. We tested the hypothesis that supplementation with choline in the postnatal period will improve working memory during adolescence in normal and ethanol-exposed animals, and that working memory engagement during adolescence will transfer to other cognitive domains and have lasting effects on executive function in adulthood. Male and female offspring of rats fed an ethanol-containing liquid diet (ET; 3%
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) or control dams given a non-ethanol liquid diet (CT) were injected with choline (Cho; 100 mg/kg) or saline (Sal) once per day from postnatal day (P) 16-P30. Animals were trained/tested on a working memory test in adolescence and then underwent attentional set shifting and reversal learning in young adulthood. In adolescence, ET rats required more training to reach criterion than CT-Sal. Choline improved working memory performance for both CT and ET animals. In young adulthood, ET animals also performed poorly on the set shifting and reversal tasks. Deficits were more robust in ET male rats than female ET rats, but Cho improved performance in both sexes. ET male rats given a combination of Cho and working memory training in adolescence required significantly fewer trials to achieve criterion than any other ET group, suggesting that early interventions can cause a persistent improvement.
Recent findings indicate that stress exposure during adolescence contributes to the development of both nicotine use and affective disorders, suggesting a potential shared biological pathway. One key ...system that may mediate the association between adolescent stress and nicotine or affective outcomes is the hypothalamic–pituitary–adrenal (HPA) axis. Here we reviewed evidence regarding the effects of adolescent stress on nicotine responses and affective phenotypes and the role of the HPA‐axis in these relationships. Literature indicates that stress, possibly via HPA‐axis dysfunction, is a risk factor for both nicotine use and affective disorders. In rodent models, adolescent stress modulates behavioural responses to nicotine and increases the likelihood of affective disorders. The exact role that the HPA‐axis plays in altering nicotine sensitivity and affective disorder development after adolescent stress remains unclear. However, it appears likely that adolescent stress‐induced nicotine use and affective disorders are precipitated by repetitive activation of a hyperactive HPA‐axis. Together, these preclinical studies indicate that adolescent stress is a risk factor for nicotine use and anxiety/depression phenotypes. The findings summarized here suggest that the HPA‐axis mediates this relationship. Future studies that pharmacologically manipulate the HPA‐axis during and after adolescent stress are critical to elucidate the exact role that the HPA‐axis plays in the development of nicotine use and affective disorders following adolescent stress.
This review examines the preclinical literature on how adolescent stress influences nicotine use and affective disorders. A model is proposed where adolescent stress initiates HPA‐axis activation to enhance nicotine use which in turn potentiates HPA‐axis activation. This cyclical relationship ultimately leads to the development of affective disorders through heightened HPA‐axis responding/sensitivity.
We examine a 6‐day traversal of the magnetotail by the ARTEMIS satellites during an interval of prolonged northward IMF. The electrostatic analyzer (ESA) onboard the ARTEMIS spacecraft measures high ...ion and electron fluxes at approximately 60 RE downtail in regions of the magnetotail which would normally be the magnetotail lobe, containing open flux evacuated of plasma. We interpret these observations as trapped plasma on closed magnetic flux indicating that the magnetotail is closed or partially closed but extends at least as far as ∼60 RE downtail. We find that the occurrence of plasma in the magnetotail and the closure of the magnetosphere results in distinct changes to the magnetotail structure including a reduction in the magnetic field strength and pressure as well as a narrowing of the tail by approximately 20 RE.
Plain Language Summary
The interplanetary magnetic field (IMF) interacts with the Earth's magnetic field which can dramatically alter the structure of the Earth's magnetosphere. When the IMF and the Earth's magnetic field are oppositely directed (i.e., southward) the magnetosphere has regions of both closed magnetic field lines near the equator where both ends of the field line connect to Earth and open magnetic field lines at the magnetic poles where one end connects to the Earth and one end connects to the IMF. Plasma populations get trapped in closed field regions and can be accelerated down to the atmosphere where they cause the aurora. Plasma populations on open field lines tend to escape out of the magnetosphere. When the IMF direction is aligned with the Earth's magnetic field (i.e., northward) the open magnetic field regions become more closed, trapping plasma. In this study, we observe trapped plasma populations 60 Earth radii down the magnetotail which coincide with observations of trapped plasma nearer to Earth indicating that the regions of closed magnetic field extend 60 Earth radii down the magnetotail.
Key Points
We examine a far magnetotail traversal (∼60 RE) by ARTEMIS during a period of prolonged northward IMF
ARTEMIS/ESA observes high density plasma ∼60 RE downtail coincident with high density plasma observed by Cluster/CIS
We interpret these observations as trapped plasma on closed field lines
A striking characteristic of cancer cells is their remarkable phenotypic plasticity, which is the ability to switch states or phenotypes in response to environmental fluctuations. Phenotypic changes ...such as a partial or complete epithelial to mesenchymal transition (EMT) that play important roles in their survival and proliferation, and development of resistance to therapeutic treatments, are widely believed to arise due to somatic mutations in the genome. However, there is a growing concern that such a deterministic view is not entirely consistent with multiple lines of evidence, which indicate that stochasticity may also play an important role in driving phenotypic plasticity. Here, we discuss how stochasticity in protein interaction networks (PINs) may play a key role in determining phenotypic plasticity in prostate cancer (PCa). Specifically, we point out that the key players driving transitions among different phenotypes (epithelial, mesenchymal, and hybrid epithelial/mesenchymal), including ZEB1, SNAI1, OVOL1, and OVOL2, are intrinsically disordered proteins (IDPs) and discuss how plasticity at the molecular level may contribute to stochasticity in phenotypic switching by rewiring PINs. We conclude by suggesting that targeting IDPs implicated in EMT in PCa may be a new strategy to gain additional insights and develop novel treatments for this disease, which is the most common form of cancer in adult men.
Abstract Background Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease ...progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. Highlights of revised RECIST 1.1 Major changes include: Number of lesions to be assessed : based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of ⩾15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10 mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5 mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes ‘unequivocal progression’ of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance : the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. Future work A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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